Leptin and insulin are essential for the regulation of food intake and metabolism. Defects in leptin and insulin action contribute to obesity and type 2 diabetes. Although considerable progress has been made, the molecular mechanisms of the actions of these two hormones are not completely understood. SH2-B, an SH2- and PH-domain containing protein, binds insulin and leptin receptors, and is tyrosyl phosphorylated in response to leptin or insulin in cultured cells. To assess the function of SH2-B in a whole organism, the SH2-B gene will be deleted in mice using homologous recombination. To determine the role of SH2-B in a leptin physiology, food intake and energy homeostasis will be examined in wild-type and SH2-B-deficient mice. To gain insight into the molecular mechanisms by which SH2-B mediates leptin action, the expression of several hypothalamic neuropeptides, target genes of peptide as well as central mediators of leptin action, will be determined. Initial signaling events downstream of the leptin receptor (including activation of JAK2, ERK1/2 and Stat3) will be examined. To assess the role of SH2- B in insulin action, carbohydrate metabolism and insulin sensitivity will be examined by measuring serum glucose and insulin, and glucose and insulin tolerance tests. To determine whether SH2-B transmits insulin signals, initial signaling events (insulin-stimulated tyrosyl phosphorylation of insulin receptor substrate proteins and activation of the phosphatidylinositol 3-kinase pathway) as well as cellular response (glucose uptake) will be examined in isolated insulin responsive cells. These studies will reveal the role of SH2-B in leptin and insulin signaling, and might identify new targets (e.g. SH2-B and it associated pathways) for therapeutic interventions of obesity and type 2 diabetes.